AUTREV-01373; No of Pages 6

Autoimmunity Reviews xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

1 Review

2 Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies

Q1 3 Cloé Comarmond, Patrice Cacoub ⁎

F
4 Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine, Université Pierre et Marie Curie, Paris 6, Paris, France
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a r t i c l e i n f o a b s t r a c t

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7 Article history: Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis and pregnancy morbidity in as- 18
8 Received 2 December 2012 sociation with the persistent presence of circulating antiphospholipid antibodies (aPL). APS remains the most 19

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9 Accepted 19 December 2012 frequent cause of acquired hypercoagulability and recurrent miscarriage. Long-term anticoagulation therapy 20
10 Available online xxxx
is the only treatment with proven benefit in the APS. Anticoagulation is not effective in all patients and carries 21
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a risk of bleeding. Recent improvements in the understanding of the pathogenic mechanisms have led to the 22

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14 Keywords:
15 Antiphospholipid syndrome
identification of potential targets and future therapies for APS. In contrast to non-specific anticoagulation, the 23
16 Pathogenesis emergence of immunomodulatory drugs provides the possibility of interfering with specific pathogenic path- 24
17 Immunotherapies ways. Novel therapies might be used in the future for APS. D 25
© 2012 Published by Elsevier B.V. 26
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31 Contents
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33 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
34 2. Pathogenesis of APS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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35 2.1. aPL antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

36 2.2. Targets for aPL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
37 3. Immunomodulatory approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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38 3.1. Hydroxychloroquine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
39 3.2. Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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40 3.3. B-cell targeted therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

41 3.4. Complement inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
42 3.5. Defibrotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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43 3.6. Antiplatelet agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

44 3.7. Inhibition of co-stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
45 3.8. Intracellular pathways inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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46 3.9. Anti-cytokine therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

47 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
48 Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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49 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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51 1. Introduction when it occurs with another autoimmune disease, mainly systemic 58

lupus erythematosus (SLE). APS is recognized as the most common 59
52 Antiphospholipid syndrome (APS) is a systemic autoimmune dis- cause of acquired thrombophilia in the general population. There is a 60
53 ease defined by recurrent thromboembolic events and/or pregnancy wide spectrum of clinical manifestations associated with procoagulant 61
54 morbidity in the presence of antiphospholipid (aPL) antibodies, phenotype of APS. Clinical features associated with aPL ranged from 62
55 including anticardiolipin antibodies (aCL), anti-β2-glycoprotein 1 non-criteria aPL manifestations in persistent aPL-positive patients 63
56 antibodies (aβ2GP1), and lupus anticoagulant (LA) [1,2]. APS can (livedo reticularis, thrombocytopenia, hemolytic anemia, skin ulcers, 64 Q3
57 be classified as primary or as secondary antiphospholipid syndrome aPL-associated nephropathy, heart valve disease), to APS with 65
only pregnancy morbidity, APS with vascular events, and to life- 66
threatening catastrophic APS (CAPS) [3–5]. While thrombotic events re- 67
⁎ Corresponding author at: AP-HP, Hôpital Pitié-Salpêtrière, Service de Médecine Interne,
Q2 Paris F-75013, France. Tel.: +33 1 42 17 80 09; fax: +33 1 42 17 80 33. lated to aPL can occur in any vascular bed, some APS patients present 68
E-mail address: patrice.cacoub@psl.aphp.fr (P. Cacoub). with only pregnancy morbidity. Considering the heterogeneity of APS 69

1568-9972/$ – see front matter © 2012 Published by Elsevier B.V.

http://dx.doi.org/10.1016/j.autrev.2012.12.006

Please cite this article as: Comarmond C, Cacoub P, Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies,
Autoimmun Rev (2013), http://dx.doi.org/10.1016/j.autrev.2012.12.006
 2 C. Comarmond, P. Cacoub / Autoimmunity Reviews xxx (2013) xxx–xxx

70 clinical manifestations, it is likely that more than one pathological Table 1 t1:1
71 process may play a role. However, current management strategies for New immunomodulatory treatments in antiphospholipid syndrome. t1:2

72 patients with APS are restricted mainly to anticoagulation therapy, Treatments Molecular Data status in Clinical References t1:3
73 which is not effective in all patients [6,7]. Despite antithrombotic ther- targets APS effects in
74 apy, up to 30% of APS patients have recurrent thrombotic events [8]. APS

75 Furthermore, patients may experience bleeding complications with Hydroxychloroquine Anx A5 Clinical trial Preventive [51] t1:4
76 conventional anticoagulation therapy (2–3%) [9]. The optimal treat- NCT01475149
Fluvastatin TF, IL6, IL1b, Clinical trial In progress [54,55] t1:5
77 ment in APS patient resistant or intolerant to long-term anticoagulation
adhesion NCT00674297
78 remains unclear. Recent improvement in the understanding of the molecules
79 pathogenic mechanisms, including aPL-induced activation of platelets, B-cell therapies t1:6
80 endothelial cells, monocytes, complement and coagulation cascade Rituximab CD20 Clinical trial Curative [69] t1:7
81 (Fig. 1), has led to the identification of potential targets and future ther- NCT00537290
(RITAPS)
82 apies for APS (Table 1).
Belimumab/BAFF BAFF-R/BAFF Mice Curative/ [70] t1:8
83 In this article, we reviewed significant advances that have been blockage Preventive

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84 made in elucidating the pathophysiology of the disease, and discuss Complement C3, C5,C6 KO mice Preventive [32,35,36] t1:9
85 new potential immunomodulatory approaches (Fig. 2). inhibition fractions or and

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C5a-R curative
Eculizumab C5a Case report Curative [73–76] t1:10
86 2. Pathogenesis of APS (CAPS)
Defibrotide TF Case report Curative [79] t1:11

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(CAPS)
87 The pathogenic mechanisms that lead to clinical manifestations as- Antiplatelet agents t1:12
88 sociated with aPL are only partially understood. The aPL-induced man- Dilazep TF In vitro No data for [80,81] t1:13

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89 ifestations of the disease are the result of many contributory factors clinical
90 (Fig. 1). features
Abciximab GPIIb/IIIa-R KO mice Curative [12] t1:14

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Co-stimulation t1:15
inhibition
91 2.1. aPL antibodies
Abatacept CD80/CD86 Mice Preventive [70,83] t1:16
(CTLA4-Ig)
D (B7)-CD28
92 Various in vitro and in vivo animal studies have shown that aPL ligation
93 antibodies are pathogenic in APS [10–12]. They increase thrombus Intracellular t1:17
94 formation in the venous and arterial circulation, and thrombogenic pathways
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inhibition
95 properties have been demonstrated in both settings [13,14]. Howev-
SB203580 p38 MAP In vitro No data for [26,28,29] t1:18
96 er, the exact mechanisms that produce these autoantibodies and kinase clinical
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97 mediate disease with thrombosis remain uncertain. Despite the het- features
98 erogeneity of aPL, similar HLA class allele associations have been MG132 or SN50 NFκB Mice, in vitro Curative [26,28,87] t1:19
Cell-surface ApoER2, Mice, in vitro Curative [23,88,89,92] t1:20
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99 identified [15]. The associations of HLA-DR4, -DR7, and -DRw53 are

receptors TLR4, Anx A2
100 the most consistent in APS patients [16]. The main autoantigen for Anti cytokine t1:21
101 aPL antibodies is β2GP1, a plasma apolipoprotein that mediates aPL therapies
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102 binding to target cells (i.e. platelets, monocytes, endothelial cells Anti-TNFα TNFα Mice Preventive [96] t1:22
Q4 103 and trophoblasts) [17–22]. Mechanisms induced by aPL antibodies
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Fig. 1. Pathogenetic model in antiphospholipid syndrome and potential targets for new therapeutic approaches. Anx: annexin, ApoER2: apolipoprotein E receptor 2, BAFF-R: B-cell acti-
vating factor receptor, C3a-R: C3a receptor, CTLA4: Cytotoxic T-Lymphocyte Antigen 4, GP IIb/IIIa: glycoprotein IIb/IIIa, ICAM-1: Intercellular Adhesion Molecule 1, IL: interleukin, MAC:
membrane attack complex, MAPK: Mitogen-activated protein (MAP) kinases, MHC II: Major Histocompatibility Complex class II, NFκB: nuclear factor-kappa B, PF4: Platelet factor 4, TBX2:
T-box transcription factor 2, TCR: T-Cell Receptor, TF: tissue factor, TLR: Toll-like receptor, TNFα: tumor necrosis factor-αVCAM-1: vascular cell adhesion molecule 1, and VEGF: Vascular
endothelial growth factor.

Please cite this article as: Comarmond C, Cacoub P, Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies,
Autoimmun Rev (2013), http://dx.doi.org/10.1016/j.autrev.2012.12.006
 C. Comarmond, P. Cacoub / Autoimmunity Reviews xxx (2013) xxx–xxx 3

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Fig. 2. Immunomodulatory therapies with clinical benefits in human antiphospholipid syndrome.

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104 leading to thrombosis and fetal loss include up-regulation of tissue loss [32,33]. C3, C5, C5a receptor or C6 knockout mice develops 144
105 factor (TF) expression on monocytes and endothelial cells (ECs) [23]. aPL-related complications less frequently [32,34–36]. 145

106 2.2. Targets for aPL

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3. Immunomodulatory approaches 146
107 The effects of aPL antibodies on hemostatic reactions include inhibi-
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108 tion of the fibrinolytic system and activation of the coagulation cascade. Intensive research in the last two decades on the pathogenic 147
109 aPL-induced overproduction of TF activates the extrinsic pathway of the mechanisms has now led to the proposal of several new therapeutic 148
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110 coagulation cascade. Blood clotting in APS involves the interaction of strategies based on targeted therapies in APS (Table 1 and Fig. 2). 149
111 aPL with annexin A5 (AnxA5), a protein found on the surface of the
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112 cells lining the blood vessels (endothelial cells). AnxA5, a potent antico-
113 agulant protein forms a shield on endothelial cell surfaces and blocks 3.1. Hydroxychloroquine 150
114 their availability for coagulation reactions. Antiphospholipid antibodies
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115 disrupt AnxA5 binding, thereby accelerating coagulation reactions. Hydroxychloroquine (HCQ) is an antimalarial drug known to have 151
116 AnxA5 resistance assay is a blood test that can detect problems with immunologic effects, including inhibition of inflammatory cytokines 152
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117 the protective AnxA5 shield on endothelial cell surfaces. (TNFα, IL1, IL2, IL6), inhibition of Toll-like receptor activation, interrup- 153
118 aPL complexes promote cellular activation of platelets, monocytes tion of antigen processing, and inhibition of TCR- and BCR-induced 154
119 and ECs. Platelet factor 4 (PF4) binds dimerized β2GP1, and this com- calcium signaling [37,38]. HCQ also has various hematologic effects. In 155
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120 plex is recognized by anti-β2GP1 antibodies. PF4-β2GP1 complexes a dose-dependent manner, HCQ inhibits platelet aggregation and ara- 156
121 activate platelets as shown by p38 MAP kinase phosphorylation, chidonic acid release from stimulated platelets [39,40]. HCQ reduces 157
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122 thromboxane B2 production and GPIIb/IIIa receptor expression. Platelet binding of antiβ2GP1 antibodies to the phospholipid bilayer [41]. In 158
123 activation leads to the clinical manifestations of both thrombocytopenia mice injected with IgG aPL compared with controls, HCQ significantly 159
124 and thrombosis in APS patients [24]. aPL enhances the expression of reduced both thrombus size and total time of thrombus formation 160
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125 platelet membrane glycoproteins (GP)IIb/IIIa [25]. There is also evi- [42]. HCQ can prevent thromboembolic events in lupus patients with 161
126 dence of monocyte and EC activation. aPL induce TF expression in or without antiphospholipid antibodies [43–46] and protect against pri- 162
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127 monocytes from APS patients through phosphorylation of p38 MAP ki- mary thrombotic event in asymptomatic aPL-positive patients [47,48]. 163
128 nase and subsequent NFκB activation [26]. It has recently been demon- In a large not yet published SLE cohort (n= 1795), current HCQ use de- 164
129 strated that aPL induce TNFα production in monocytes via the creased the risk of thrombosis, particularly in those with positive 165
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130 activation of TLR8 [27]. aPL antibodies induce EC activation and TF antiphospholipid antibodies [49]. Recent in vitro studies have demon- 166
131 upregulation through p38 MAP kinase phosphorylation and the NFκB strated that HCQ was able to restore the anticoagulant action of 167
132 pathway [28,29]. In vitro studies have shown that EC express increased AnxA5, which is reduced in the presence of aPL antibodies [50,51]. An 168
133 levels of adhesion molecules (ICAM-1, VCAM-1, E-selectin) when ongoing clinical trial (NCT01475149) is assessing the effect of HCQ on 169
134 incubated with aPL antibodies [30]. Several proinflammatory and AnxA5 resistance assay in aPL-positive patients with and without 170
135 prothrombotic markers (IL-1b, IL-6, IL-8, TNFα, VEGF, TF, CAM) in APL systemic lupus. The primary goal of the study is to compare results of 171
136 have been studied in animal models and/or in vitro. An ongoing study the AnxA5 resistance assay from patients before and after taking HCQ 172
137 have identified various biomarkers differentially up-regulated in for 12 weeks. The secondary goal is to measure a variety of other 173
138 aPL-positive patients with evidence of autoimmune disease (PAPS and blood tests including D-dimer, activated protein C resistance, and aPL 174
139 SLE) compared to “asymptomatic” aPL subjects [31]. titers/status (LA test, aCL ELISA, aβ2GP1 ELISA, and anti-Domain-I 175
140 Activation of the complement system by aPL antibodies promotes a β2GP1 ELISA). Recent consensus guidelines recommend the combina- 176
141 hypercoagulable state. In a mouse model of APS using high-titer APS tion of HCQ and low-molecular-weight heparin in recurrent APS [9]. 177
142 human serum, complement activation (especially interactions between However, further controlled studies are needed to determine the effec- 178
143 C5a and its receptor) was found to be essential in aPL-mediated fetal tiveness of HCQ in preventing thrombosis in APS. 179

Please cite this article as: Comarmond C, Cacoub P, Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies,
Autoimmun Rev (2013), http://dx.doi.org/10.1016/j.autrev.2012.12.006
 4 C. Comarmond, P. Cacoub / Autoimmunity Reviews xxx (2013) xxx–xxx

180 3.2. Statins [77,78]. Successful treatment using defibrotide in refractory CAPS has 239
been reported [66,79]. 240
181 Statins are cholesterol-lowering agents that also have anti-
182 inflammatory properties. Statins have a direct effect on the endothelial 3.6. Antiplatelet agents 241
183 expression of adhesion molecules, plaque formation and thromboxane
184 synthesis. aPL antibodies induce increased expression, function and tran- Dilazep, an antiplatelet agent, is generally used as an antithrombotic 242
185 scription of tissue factor on ECs. Activation of ECs and thrombogenicity of drug in clinical practice. Dilazep is also known to exert cytoprotective 243
186 aPL in vivo can be reversed by treatment with statins in experimental and antioxidant effects on ECs. It can inhibit TF expression in ECs and 244
187 models [52,53]. After one month of 20 mg/day fluvastatin administration monocytes, and may be a good candidate in the treatment of APS. 245
188 in APS patients with thrombosis, significant inhibition of both p38 MAP [80,81]. 246
189 kinase and NFκB activities was observed. Tissue factor was down- aPL-mediated thrombophilia has not been observed in GPIIb/ 247
190 regulated with the inhibition of different prothrombotic biomarkers IIIa-deficient mice [12]. Furthermore, aPL-enhanced thrombosis in 248
191 after fluvastatin treatment [54]. Based on the preliminary analysis of a vivo can be abrogated by infusions of a GPIIb/IIIa antagonist (1B5) 249
192 pilot study, the administration of fluvastatin 40 mg daily for 3 months monoclonal antibody. Abciximab (a specific GPIIb/IIIa receptor inhibi- 250

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193 showed a significant reduction of pro-inflammatory and prothrombotic tor) could be useful for APS treatment. Data from a Japanese study 251
194 biomarkers in persistently aPL-positive patients, with or without SLE showed that dual antiplatelet therapy may be effective for secondary 252

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195 [55]. These findings provide further support for the potential beneficial prevention of arterial thrombosis in patients with APS [82]. 253
196 effects of statins in aPL-positive patients, justifying further controlled
197 clinical studies.

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3.7. Inhibition of co-stimulation 254

198 3.3. B-cell targeted therapies

In contrast to BAFF-R inhibition, costimulatory blockade with cy- 255

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totoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4-Ig) showed 256
199 It has been suggested that B cells contribute to APS pathogenesis
no curative effect but was able to prevent B cell activation and aPL 257
200 through the production of aPL. In both human and murine studies,
antibody production when administered before aPL antibody develop- 258

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201 B-cell directed therapies in APS appeared to have beneficial serologic
ment [70]. CTLA4-Ig only has a preventive effect [83]. Abatacept is a 259
202 and clinical effects [56].
fusion protein composed of the Fc region of IgG1 fused to the extracel- 260
203 Based on several case reports [56–64], rituximab (an anti-CD20 chi-
lular domain of CTLA4. Containing a high-affinity binding site for
D 261
204 meric monoclonal antibody) has been shown to be effective in the treat-
B7 protein (CD80/CD86) on antigen-presenting cells, abatacept is a 262
205 ment of thrombocytopenia, hemolytic anemia, skin ulcers, and diffuse
selective co-stimulation modulator, as it inhibits the costimulation of 263
206 alveolar hemorrhage in primary APS. The benefits of rituximab have
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T-cells. This treatment is currently approved for refractory rheumatoid 264
207 also been described in a few cases of CAPS [60,65–67]. A Spanish multi-
arthritis patients [84,85]. No report on the efficacy of abatacept in APS 265
208 center study (BIOGEAS project) reports a 92% therapeutic response
patients was found. 266
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209 with the use of rituximab in patients with APS [68]. An open-label
210 phase IIa pilot study (RITAPS) assessed the effectiveness and safety of
3.8. Intracellular pathways inhibition 267
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211 rituximab in 20 patients with anticoagulation-resistant manifestations

212 associated with aPL and no other systemic autoimmune disease [69].
213 B cell depletion therapy with rituximab may be a promising therapy The aPL-induced prothrombotic state involves numerous proteins 268
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214 for patients with APS. and intracellular pathways. Specific intracellular pathway inhibition re- 269
215 B-cell-activating factor (BAFF, also known as tumor necrosis factor duces aPL-induced monocyte and EC activation and/or TF upregulation. 270
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216 ligand superfamily, member 13b) antagonist can prevent, in a mouse Many different stimuli (infectious agents, stress) can activate p38 271
217 model of APS, the onset of disease, whereas BAFF-R blockade im- MAP kinase, an important component of intracellular signaling cas- 272
218 proves the outcome by reducing renal and cardiac injury, and increas- cades that initiates various inflammatory cellular responses. In vitro, 273
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219 ing survival [70]. Belimumab (BLyS-specific inhibitor), a human IgG aPL induced a significant increase in TF activity in EC and mono- 274
220 monoclonal antibody that inhibits BAFF, is now approved for SLE cytes, involving phosphorylation of p38 MAP kinase and activation 275
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221 treatment [56,71,72]. To our knowledge, it has never been studied of NFκB. These processes were inhibited by SB203580 (a specific in- 276
222 in patients with APS. hibitor of p38 MAP kinase) [26,28]. 277
NFκB is a cytoplasmic transcription factor expressed by most cells. 278
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223 3.4. Complement inhibition In vitro, NFκB has been shown to be an essential intermediate in the 279
activation of ECs by anti-β2GP1 antibodies [86]. In vivo and in vitro 280
studies demonstrated that specific inhibition of NFκB by MG132 or 281
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224 Increased complement activation has been implicated in the path-

225 ogenesis of APS in animal models. Studies in murine models showed SN50 (a specific inhibitor of NFκB) attenuated aPL-induced thrombo- 282
226 that a more targeted intervention, such as complement inhibition, sis and EC or monocyte activation [26,28,87]. 283
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227 may be an effective means of preventing aPL-induced thrombosis Inhibition of cell-surface receptors including ApoER2, TLR4 via the 284
Q5 228 and improving APS-related manifestations [32,35,36]. Eculizumab is MyD88 pathway, and AnxA2 reduced aPL-mediated pathogenic effects 285
229 a humanized monoclonal antibody directed against complement in animal models, both in vitro and in vivo [23,88–91]. More recently, 286
230 protein C5, which inhibits its cleavage to C5a and C5b and prevents a blocker of signaling transduction mediated by the intracellular do- 287
231 of membrane attack complex. Recently, a few case reports have de- main of TLR4 was found to decrease TF, MyD88 and TNF expression [92]. 288
232 scribed the benefits of eculizumab therapy in CAPS patients who
233 were refractory to conventional therapy or for the prevention of re- 3.9. Anti-cytokine therapies 289
234 current CAPS after renal transplantation [66,73–76].
aPL induce significant increases in proinflammatory cytokines such 290
235 3.5. Defibrotide as IL-1, IL-6, IL-8 and TNF-α [93–95]. In a murine model, TNF-α released 291
in response to complement activation was identified as a critical medi- 292
236 Defibrotide is an adenosine receptor agonist that blocks monocyte ator of aPL antibodies-induced injury. Based on the fetal protective ef- 293
237 TF expression. It is used for the treatment of severe hepatic veno- fects of TNF-α deficiency and TNF blockade in mice treated with aPL 294
238 occlusive disease and multiorgan failure after stem cell transplantation antibodies, inhibitors of TNF-α may provide effective treatment for 295

Please cite this article as: Comarmond C, Cacoub P, Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies,
Autoimmun Rev (2013), http://dx.doi.org/10.1016/j.autrev.2012.12.006
 C. Comarmond, P. Cacoub / Autoimmunity Reviews xxx (2013) xxx–xxx 5

296 some patients with APS and recurrent pregnancy loss [96]. Such treat- [19] Pengo V, Banzato A, Denas G, et al. Correct laboratory approach to APS diagnosis and 369
297 ment could not be used in APS secondary to SLE. monitoring. Autoimmun Rev December 3 2012, doi:10.1016/j.autrev.2012.11.008 370
[Published Online First]. 371
[20] Mirarabshahi P, Abdelatti M, Krilis S. Post-translational oxidative modification of 372
298 4. Conclusion β2-glycoprotein I and its role in the pathophysiology of the antiphospholipid syn- 373
drome. Autoimmun Rev 2012;11:779–80. 374
[21] Meijide H, Sciascia S, Sanna G, et al. The clinical relevance of IgA anticardiolipin 375
299 The only validated treatment for APS is life-long anticoagulation. and IgA anti-β2 glycoprotein I antiphospholipid antibodies: a systematic review. 376
300 Antithrombotic medications are currently use to prevent thrombo- Autoimmun Rev August 19 2012, doi:10.1016/j.autrev.2012.08.002 [Published 377
301 embolic events in patients with APS, but there is undoubtedly a Online First]. 378
[22] Chamorro A-J, Marcos M, Mirón-Canelo J-A, et al. Val247Leu β2-glycoprotein-I al- 379
302 need to develop alternative therapies for this autoimmune disease. lelic variant is associated with antiphospholipid syndrome: systematic review 380
303 Based on recent advances in the pathophysiology of APS, modulation and meta-analysis. Autoimmun Rev 2012;11:705–12. 381
304 of the immune response may be valuable for the development of new [23] Zhou H, Yan Y, Xu G, et al. Toll-like receptor (TLR)-4 mediates anti- 382
β2GPI/β2GPI-induced tissue factor expression in THP-1 cells. Clin Exp 383
305 therapeutic modalities to treat and/or prevent thrombosis in APS pa- Immunol 2011;163:189–98. 384
306 tients. To date, few human data are available to support these innova- [24] Sikara MP, Routsias JG, Samiotaki M, et al. {beta}2 Glycoprotein I ({beta}2GPI) binds 385
307 tive approaches. platelet factor 4 (PF4): implications for the pathogenesis of antiphospholipid syn- 386

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drome. Blood 2010;115:713–23. 387
[25] Espinola RG, Pierangeli SS, Gharavi AE, et al. Hydroxychloroquine reverses 388
platelet activation induced by human IgG antiphospholipid antibodies. Thromb 389

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Haemost 2002;87:518–22. 390
308 Take-home messages [26] López-Pedrera C, Buendía P, Cuadrado MJ, et al. Antiphospholipid antibodies from 391
309 patients with the antiphospholipid syndrome induce monocyte tissue factor ex- 392
393

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pression through the simultaneous activation of NF-kappaB/Rel proteins via the
310 • Recent studies on APS pathogenesis opened a new era of targeted
p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway. 394
311 therapy. Arthritis Rheum 2006;54:301–11. 395
312 • Immunomodulatory approaches hold great therapeutic potential in APS [27] Döring Y, Hurst J, Lorenz M, et al. Human antiphospholipid antibodies induce 396

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313 patients who are resistant or intolerant to long-term anticoagulation. TNFalpha in monocytes via Toll-like receptor 8. Immunobiology 2010;215: 397
230–41. 398
314 • Clinical trials are needed to define the role of immunomodulatory [28] Vega-Ostertag M, Casper K, Swerlick R, et al. Involvement of p38 MAPK in the 399

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317 targeted therapies in APS treatment. up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies. 400
316 Arthritis Rheum 2005;52:1545–54. 401
[29] Vega-Ostertag ME, Ferrara DE, Romay-Penabad Z, et al. Role of p38 mitogen-activated 402
Q6 318 References protein kinase in antiphospholipid antibody-mediated thrombosis and endothelial 403
cell activation. J Thromb Haemost 2007;5:1828–34. 404
319 [1] Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an
D
[30] Simantov R, Lo SK, Gharavi A, et al. Antiphospholipid antibodies activate vascular 405
320 update of the classification criteria for definite antiphospholipid syndrome (APS). endothelial cells. Lupus 1996;5:440–1. 406
321 J Thromb Haemost 2006;4:295–306. [31] Basra G, Erkan D, Willis R, et al. Pro-inflammatory and pro-thrombotic markers in 407
E
322 [2] Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on pre- persistently antiphospholipid antibody-positive patients with or without system- 408
323 liminary classification criteria for definite antiphospholipid syndrome: report of ic lupus erythematosus. ACR [abstract# 2456]; 2012. 409
324 an international workshop. Arthritis Rheum 1999;42:1309–11. [32] Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils 410
T

325 [3] Galarza-Maldonado C, Kourilovitch MR, Pérez-Fernández OM, et al. Obstetric mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003;112: 411
326 antiphospholipid syndrome. Autoimmun Rev 2012;11:288–95. 1644–54. 412
327 [4] Cervera R, Conti F, Doria A, et al. Does seronegative antiphospholipid syndrome [33] Pierangeli SS, Girardi G, Vega-Ostertag M, et al. Requirement of activation of com- 413
C

328 really exist? Autoimmun Rev 2012;11:581–4. plement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. 414
329 [5] Staub HL, Bertolaccini ML, Khamashta MA. Anti-phosphatidylethanolamine anti- Arthritis Rheum 2005;52:2120–4. 415
330 body, thromboembolic events and the antiphospholipid syndrome. Autoimmun [34] Romay-Penabad Z, Liu XX, Montiel-Manzano G, et al. C5a receptor-deficient mice 416
E

331 Rev 2012;12:230–4. are protected from thrombophilia and endothelial cell activation induced by some 417
332 [6] Pengo V, Ruiz-Irastorza G, Denas G, et al. High intensity anticoagulation in antiphospholipid antibodies. Ann N Y Acad Sci 2007;1108:554–66. 418
333 the prevention of the recurrence of arterial thrombosis in antiphospholipid [35] Carrera-Marín AL, Romay-Penabad Z, Papalardo E, et al. C6 knock-out mice are 419
R

334 syndrome: ‘PROS’ and ‘CONS’. Autoimmun Rev 2012;11:577–80. protected from thrombophilia mediated by antiphospholipid antibodies. Lupus 420
335 [7] Ceccarelli F, Chighizola C, Finazzi G, et al. Thromboprophylaxis in carriers of August 29 2012, doi:10.1177/0961203312458839 [Published Online First]. 421
336 antiphospholipid antibodies (APL) without previous thrombosis: ‘Pros’ and ‘Cons’. [36] Holers VM, Girardi G, Mo L, et al. Complement C3 activation is required for 422
337 423
R

Autoimmun Rev 2012;11:568–71. antiphospholipid antibody-induced fetal loss. J Exp Med 2002;195:211–20.
338 [8] Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the [37] Lombard-Platlet S, Bertolino P, Deng H, et al. Inhibition by chloroquine of the class II 424
339 antiphospholipid-antibody syndrome. N Engl J Med 1995;332:993–7. major histocompatibility complex-restricted presentation of endogenous antigens 425
340 [9] Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidence-based recommendations varies according to the cellular origin of the antigen-presenting cells, the nature of 426
O

341 for the prevention and long-term management of thrombosis in antiphospholipid the T-cell epitope, and the responding T cell. Immunology 1993;80:566–73. 427
342 antibody-positive patients: report of a task force at the 13th International Congress [38] Goldman FD, Gilman AL, Hollenback C, et al. Hydroxychloroquine inhibits calcium 428
343 on antiphospholipid antibodies. Lupus 2011;20:206–18. signals in T cells: a new mechanism to explain its immunomodulatory properties. 429
C

344 [10] Jankowski M, Vreys I, Wittevrongel C, et al. Thrombogenicity of beta 2-glycoprotein Blood 2000;95:3460–6. 430
345 I-dependent antiphospholipid antibodies in a photochemically induced thrombosis [39] Yoon KH. Sufficient evidence to consider hydroxychloroquine as an adjunct therapy 431
346 model in the hamster. Blood 2003;101:157–62. in antiphospholipid antibody (Hughes') syndome. J Rheumatol 2002;29:1574–5. 432
347 433
N

[11] Pierangeli SS, Colden-Stanfield M, Liu X, et al. Antiphospholipid antibodies from [40] Jancinová V, Nosál R, Petríková M. On the inhibitory effect of chloroquine on blood
348 antiphospholipid syndrome patients activate endothelial cells in vitro and in platelet aggregation. Thromb Res 1994;74:495–504. 434
349 vivo. Circulation 1999;99:1997–2002. [41] Rand JH, Wu X-X, Quinn AS, et al. Hydroxychloroquine directly reduces the bind- 435
350 [12] Pierangeli SS, Liu XW, Barker JH, et al. Induction of thrombosis in a mouse model ing of antiphospholipid antibody-beta2-glycoprotein I complexes to phospholipid 436
U

351 by IgG, IgM and IgA immunoglobulins from patients with the antiphospholipid bilayers. Blood 2008;112:1687–95. 437
352 syndrome. Thromb Haemost 1995;74:1361–7. [42] Edwards MH, Pierangeli S, Liu X, et al. Hydroxychloroquine reverses thrombogenic 438
353 [13] Gharavi AE, Pierangeli SS, Colden-Stanfield M, et al. GDKV-induced antiphospholipid properties of antiphospholipid antibodies in mice. Circulation 1997;96:4380–4. 439
354 antibodies enhance thrombosis and activate endothelial cells in vivo and in vitro. [43] Wallace DJ. Antimalarial agents and lupus. Rheum Dis Clin North Am 1994;20:243–63. 440
355 J Immunol 1999;163:2922–7. [44] Jung H, Bobba R, Su J, et al. The protective effect of antimalarial drugs on 441
356 [14] Pierangeli SS, Liu SW, Anderson G, et al. Thrombogenic properties of murine thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 442
357 anti-cardiolipin antibodies induced by beta 2 glycoprotein 1 and human immuno- 2010;62:863–8. 443
358 globulin G antiphospholipid antibodies. Circulation 1996;94:1746–51. [45] Tektonidou MG, Laskari K, Panagiotakos DB, et al. Risk factors for thrombosis and 444
359 [15] Domenico Sebastiani G, Minisola G, Galeazzi M. HLA class II alleles and genetic pre- primary thrombosis prevention in patients with systemic lupus erythematosus 445
360 disposition to the antiphospholipid syndrome. Autoimmun Rev 2003;2:387–94. with or without antiphospholipid antibodies. Arthritis Rheum 2009;61:29–36. 446
361 [16] Dagenais P, Urowitz MB, Gladman DD, et al. A family study of the antiphospholipid [46] Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus 447
362 syndrome associated with other autoimmune diseases. J Rheumatol 1992;19: erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol 448
363 1393–6. Rep 2011;13:77–80. 449
364 [17] Roggenbuck D, Egerer K, Von Landenberg P, et al. Antiphospholipid antibody [47] Shah NM, Khamashta MA, Atsumi T, et al. Outcome of patients with anticardiolipin 450
365 profiling: time for a new technical approach? Autoimmun Rev 2012;11:821–6. antibodies: a 10 year follow-up of 52 patients. Lupus 1998;7:3–6. 451
366 [18] Mahler M, Norman GL, Meroni PL, et al. Autoantibodies to domain 1 of beta 2 [48] Kaiser R, Cleveland CM, Criswell LA. Risk and protective factors for thrombosis in sys- 452
367 glycoprotein 1: a promising candidate biomarker for risk management in temic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum 453
368 antiphospholipid syndrome. Autoimmun Rev 2012;12:313–7. Dis 2009;68:238–41. 454

Please cite this article as: Comarmond C, Cacoub P, Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies,
Autoimmun Rev (2013), http://dx.doi.org/10.1016/j.autrev.2012.12.006
 6 C. Comarmond, P. Cacoub / Autoimmunity Reviews xxx (2013) xxx–xxx

455 [49] Law G, Magder L, Fang H, et al. Hydroxychloroquine reduces thrombosis in [73] Shapira I, Andrade D, Allen SL, et al. Brief report: induction of sustained remission 525
456 systemic lupus erythematosus, particularly in antiphospholipid positive patient. in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal 526
Q7 457 Arthritis Rheum 2012 [Abstract]. complement with eculizumab. Arthritis Rheum 2012;64:2719–23. 527
458 [50] Wu X-X, Guller S, Rand JH. Hydroxychloroquine reduces binding of antiphospholipid [74] Lonze BE, Singer AL, Montgomery RA. Eculizumab and renal transplantation in a 528
459 antibodies to syncytiotrophoblasts and restores annexin A5 expression. Am J Obstet patient with CAPS. N Engl J Med 2010;362:1744–5. 529
460 Gynecol 2011;205:576.e7–576.e14. [75] Velik-Salchner C, Lederer W, Wiedermann F. Eculizumab and renal transplanta- 530
461 [51] Rand JH, Wu X-X, Quinn AS, et al. Hydroxychloroquine protects the annexin A5 tion in a patient with catastrophic antiphospholipid syndrome: effect of heparin 531
462 anticoagulant shield from disruption by antiphospholipid antibodies: evidence on complement activation. Lupus 2011;20:772. 532
463 for a novel effect for an old antimalarial drug. Blood 2010;115:2292–9. [76] Hadaya K, Ferrari-Lacraz S, Fumeaux D, et al. Eculizumab in acute recurrence of 533
464 [52] Ferrara DE, Swerlick R, Casper K, et al. Fluvastatin inhibits up-regulation of tissue thrombotic microangiopathy after renal transplantation. Am J Transplant 2011;11: 534
465 factor expression by antiphospholipid antibodies on endothelial cells. J Thromb 2523–7. 535
466 Haemost 2004;2:1558–63. [77] Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic 536
467 [53] Girardi G. Pravastatin prevents miscarriages in antiphospholipid antibody-treated veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an 537
468 mice. J Reprod Immunol 2009;82:126–31. open-label, phase 3, randomised controlled trial. Lancet 2012;379:1301–9. 538
469 [54] López-Pedrera C, Ruiz-Limón P, Aguirre MÁ, et al. Global effects of fluvastatin on the [78] Richardson PG, Soiffer RJ, Antin JH, et al. Defibrotide for the treatment of severe 539
470 prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis hepatic veno-occlusive disease and multiorgan failure after stem cell transplanta- 540
471 2011;70:675–82. tion: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant 541
472 [55] Murthy VL, Erkan D, Jajoria P, et al. Effects of fluvastatin on pro-inflammatory and 2010;16:1005–17. 542
473 543

F
pro-thrombotic markers in antiphospholipid antibody (aPL)-positive patients: [79] Burcoglu-O'Ral A, Erkan D, Asherson R. Treatment of catastrophic antiphospholipid
474 preliminary results from an open-label prospective pilot study. Arthritis Rheum syndrome with defibrotide, a proposed vascular endothelial cell modulator. 544
475 2011;63(Suppl. 10):726 [abstract]. J Rheumatol 2002;29:2006–11. 545

O
476 [56] Khattri S, Zandman-Goddard G, Peeva E. B-cell directed therapies in antiphospholipid [80] Zhou H. Dilazep and dipyridamole inhibit tissue factor expression on monocytes 546
477 antibody syndrome—new directions based on murine and human data. Autoimmun induced by IgG from patients with antiphospholipid syndrome. Acta Pharmacol 547
478 Rev 2012;11:717–22. Sin 2004;25:1366–71. 548
479 [57] Erre GL, Pardini S, Faedda R, et al. Effect of rituximab on clinical and laboratory [81] Deguchi H, Takeya H, Wada H, et al. Dilazep, an antiplatelet agent, inhibits tissue 549

O
480 features of antiphospholipid syndrome: a case report and a review of literature. factor expression in endothelial cells and monocytes. Blood 1997;90:2345–56. 550
481 Lupus 2008;17:50–5. [82] Fujieda Y, Amengual O, Watanabe T, et al. Dual antiplatelet therapy as prophylaxis 551
482 [58] Chalam KV, Gupta SK, Agarwal S. Rituximab effectively reverses papilledema as- of recurrent arterial thrombosis in patients with antiphospholipid syndrome. 552
553 Q8

R
483 sociated with cerebral venous sinus thrombosis in antiphospholipid antibody Arthritis Rheum 2012 [Abstract].
484 syndrome. Eur J Ophthalmol 2007;17:867–70. [83] Akkerman A, Huang W, Wang X, et al. CTLA4Ig prevents initiation but not evolution 554
485 [59] Scheiman Elazary A, Klahr PP, Hershko AY, et al. Rituximab induces resolution of of anti-phospholipid syndrome in NZW/BXSB mice. Autoimmunity 2004;37:445–51. 555
486 recurrent diffuse alveolar hemorrhage in a patient with primary antiphospholipid [84] Genovese MC, Becker J-C, Schiff M, et al. Abatacept for rheumatoid arthritis refrac- 556

P
487 antibody syndrome. Lupus 2012;21:438–40. tory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353:1114–23. 557
488 [60] Rubenstein E, Arkfeld DG, Metyas S, et al. Rituximab treatment for resistant [85] Genovese MC, Schiff M, Luggen M, et al. Efficacy and safety of the selective 558
489 antiphospholipid syndrome. J Rheumatol 2006;33:355–7. co-stimulation modulator abatacept following 2 years of treatment in patients 559
490 [61] Costa R, Fazal S, Kaplan RB, et al. Successful plasma exchange combined with with rheumatoid arthritis and an inadequate response to anti-tumour necrosis
D 560
491 rituximab therapy in aggressive APS-related cutaneous necrosis. Clin Rheumatol factor therapy. Ann Rheum Dis 2008;67:547–54. 561
492 June 17 2010, doi:10.1007/s10067-010-1506-3 [Published Online First]. [86] Dunoyer-Geindre S, De Moerloose P, Galve-de Rochemonteix B, et al. NFkappaB is an es- 562
493 [62] Rückert A, Glimm H, Lübbert M, et al. Successful treatment of life-threatening Evans sential intermediate in the activation of endothelial cells by anti-beta(2)-glycoprotein 1 563
E
494 syndrome due to antiphospholipid antibody syndrome by rituximab-based regimen: antibodies. Thromb Haemost 2002;88:851–7. 564
495 a case with long-term follow-up. Lupus 2008;17:757–60. [87] Montiel-Manzano G, Romay-Penabad Z, Papalardo de Martínez E, et al. In vivo 565
496 [63] Trappe R, Loew A, Thuss-Patience P, et al. Successful treatment of thrombocytope- effects of an inhibitor of nuclear factor-kappa B on thrombogenic properties of 566
T

497 nia in primary antiphospholipid antibody syndrome with the anti-CD20 antibody antiphospholipid antibodies. Ann N Y Acad Sci 2007;1108:540–53. 567
498 rituximab—monitoring of antiphospholipid and anti-GP antibodies: a case report. [88] Romay-Penabad Z, Montiel-Manzano MG, Shilagard T, et al. Annexin A2 is involved 568
499 Ann Hematol 2006;85:134–5. in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo. 569
C

500 [64] Sciascia S, Naretto C, Rossi D, et al. Treatment-induced downregulation of Blood 2009;114:3074–83. 570
501 antiphospholipid antibodies: effect of rituximab alone on clinical and laboratory [89] Romay-Penabad Z, Aguilar-Valenzuela R, Urbanus RT, et al. Apolipoprotein E re- 571
502 features of antiphospholipid syndrome. Lupus 2011;20:1106–8. ceptor 2 is involved in the thrombotic complications in a murine model of the 572
503 573
E

[65] Nageswara Rao AA, Arteaga GM, Reed AM, et al. Rituximab for successful manage- antiphospholipid syndrome. Blood 2011;117:1408–14.
504 ment of probable pediatric catastrophic antiphospholipid syndrome. Pediatr Blood [90] Meroni PL, Raschi E, Testoni C, et al. Innate immunity in the antiphospholipid 574
505 Cancer 2009;52:536–8. syndrome: role of toll-like receptors in endothelial cell activation by antiphospholipid 575
506 576
R

[66] Espinosa G, Berman H, Cervera R. Management of refractory cases of catastrophic antibodies. Autoimmun Rev 2004;3:510–5.
507 antiphospholipid syndrome. Autoimmun Rev 2011;10:664–8. [91] Mulla MJ, Brosens JJ, Chamley LW, et al. Antiphospholipid antibodies induce a 577
508 [67] Iglesias-Jiménez E, Camacho-Lovillo M, Falcón-Neyra D, et al. Infant with probable pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 578
509 catastrophic antiphospholipid syndrome successfully managed with rituximab. pathway. Am J Reprod Immunol 2009;62:96–111. 579
R

510 Pediatrics 2010;125:e1523–8. [92] Xie H, Zhou H, Wang H, et al. Anti-β(2)GPI/β(2)GPI induced TF and TNF-α expres- 580
511 [68] Ramos-Casals M, Brito-Zerón P, Muñoz S, et al. A systematic review of the off-label sion in monocytes involving both TLR4/MyD88 and TLR4/TRIF signaling path- 581
512 use of biological therapies in systemic autoimmune diseases. Medicine (Baltimore) ways. Mol Immunol 2013;53:246–54. 582
O

513 2008;87:345–64. [93] Forastiero RR, Martinuzzo ME, De Larrañaga GF. Circulating levels of tissue factor 583
514 [69] Erkan D, Vega J, Ramon G, et al. A pilot open label phase II trial of rituximab for and proinflammatory cytokines in patients with primary antiphospholipid syn- 584
515 non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum drome or leprosy related antiphospholipid antibodies. Lupus 2005;14:129–36. 585
516 November 2 2012, doi:10.1002/art.37759 [Published Online First]. [94] Soltesz P, Der H, Veres K, et al. Immunological features of primary anti-phospholipid 586
C

517 [70] Kahn P, Ramanujam M, Bethunaickan R, et al. Prevention of murine antiphospholipid syndrome in connection with endothelial dysfunction. Rheumatology (Oxford) 587
518 syndrome by BAFF blockade. Arthritis Rheum 2008;58:2824–34. 2008;47:1628–34. 588
519 [71] Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in pa- [95] Bernales I, Fullaondo A, Marín-Vidalled MJ, et al. Innate immune response gene ex- 589
N

520 tients with active systemic lupus erythematosus: a randomised, placebo-controlled, pression profiles characterize primary antiphospholipid syndrome. Genes Immun 590
521 phase 3 trial. Lancet 2011;377:721–31. 2008;9:38–46. 591
522 [72] Merrill JT, Ginzler EM, Wallace DJ, et al. Long-term safety profile of belimumab [96] Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy 592
U

523 plus standard therapy in patients with systemic lupus erythematosus. Arthritis in antiphospholipid antibody-induced pregnancy loss. J Immunol 2005;174:485–90. 593
524 Rheum 2012;64:3364–73. 594
595

Please cite this article as: Comarmond C, Cacoub P, Antiphospholipid syndrome: From pathogenesis to novel immunomodulatory therapies,
Autoimmun Rev (2013), http://dx.doi.org/10.1016/j.autrev.2012.12.006